title: Highly immunostimulatory RNA derived from a Sendai virus defective viral genome.
abstract: Defective viral genomes (DVGs) are generated during virus replication. DVGs bearing complementary ends are strong inducers of dendritic cell (DC) maturation and of the expression of antiviral and pro-inflammatory cytokines by triggering signaling of the RIG-I family of intracellular pattern recognition receptors. Our data show that DCs stimulated with virus containing DVGs have an enhanced ability to activate human T cells and can induce adaptive immunity in mice. In addition, we describe the generation of a short Sendai virus (SeV)-derived DVG RNA (DVG-324) that maintains strong immunostimulatory activity in vitro and in vivo. DVG-324 induced high levels of Ifnb expression when transfected into cells and triggered fast expression of pro-inflammatory cytokines and mobilization of dendritic cells when injected into the footpad of mice. Importantly, DVG-324 enhanced the production of antibodies to a prototypic vaccine after a single intramuscular immunization in mice. Notably, the pro-inflammatory cytokine profile induced by DVG-324 was different from that induced by poly I:C, the only viral RNA analog currently used as an immunostimulant in vivo, suggesting a distinct mechanism of action. SeV-derived oligonucleotides represent novel alternatives to be harnessed as potent adjuvants for vaccination.
authors.affiliation: Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States.
authors.forename: Xiomara
authors.initials: X
authors.lastname: Mercado-López
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Cotter
authors.forename: Won-Keun
authors.initials: WK
authors.lastname: Kim
authors.forename: Yan
authors.initials: Y
authors.lastname: Sun
authors.forename: Luis
authors.initials: L
authors.lastname: Muñoz
authors.forename: Karla
authors.initials: K
authors.lastname: Tapia
authors.forename: Carolina B
authors.initials: CB
authors.lastname: López
mesh_terms: D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D016207:Cytokines / Q000378:metabolism; D003673:Defective Viruses / Q000235:genetics / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology* / Q000821:virology; D007273:Injections, Intramuscular; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D012367:RNA, Viral / Q000235:genetics / Q000276:immunology*; D029082:Sendai virus / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D014765:Viral Vaccines / Q000008:administration & dosage / Q000276:immunology
chemical_list: D000914:Antibodies, Viral; D016207:Cytokines; D012367:RNA, Viral; D014765:Viral Vaccines
keywords: Adjuvant; DPs; DVG; Defective genomes; Dendritic cells; IFN; Immunization; MDA5; RIG-I; RIG-I-like receptors; RLRs; RSV; SeV; SeV HD; SeV LD; SeV depleted of defective particles; SeV high content of defective particles; Sendai virus; defective particles; defective virus genome; interferon; melanoma differentiation-associated protein 5; poly I:C; polyinosinic:polycytidylic acid; respiratory syncytial virus: inRSV, formalin-inactivated RSV; retinoic acid-inducible gene 1